1. Field of the Invention
The present invention relates to the use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives and, in particular, 1-diethylaminoethyl-3-quinoxaline-2-on derivatives of the formula 
wherein R3 is hydroxy, methoxy, ethoxy or hydrogen, or pharmaceutically acceptable salts thereof, for the preparation of novel pharmaceutical compositions.
2. Description of the Prior Art
The pharmaceutical activity of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives has been known for many years and, in particular, 1-diethylaminoethyl-3-(p-methoxybenzyl)-1,2-dihydroquinoxaline-1-on, whose non-proprietary name is Caroverine, has already been employed as an effective spasmolyticum in the gastrointestinal region. In that case, the efficacy of that substance is attributed, in particular, to its calcium-blocking properties, blocking the calcium-mediated activation of myofibrillar ATP.
EP-A 0 032 564 describes the use of Caroverine or its pharmaceutically safe salts for a plurality of angiocardiopathies and as a preparation for inhibiting platelet aggregation in human blood, as a preparation enhancing blood circulation and also as a substance for treating angina pectoris, myocardial infarctions, hypertonic conditions and the like. The effect of Caroverine in EP-A 0 032 564 was attributed to the fact that it is a specific Ca antagonist and that Caroverine is capable of inhibiting up to 50% of the Ca2+ ion flux into cells.
In Subsidia med. 22, 3, pages 78-85 (1970) Mxc3x6slinger reported that Caroverine could suppress epileptic seizures. Also the use of Caroverine in the treatment of acute alcohol withdrawal symptoms and its application in alkaloid withdrawal symptoms have already been described.
From EP-A 0 542 689, the use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives as neuroprotective substances is to be taken, its use in glutamate-induced and glutamate-receptor-mediated neurotoxic dysfunctions and functional disorders of the central nervous system and, in particular, of the internal ear and of the retina being particularly described. That document also speaks of the use of those substances for treating degenerative processes of neurons in the central nervous system such as, for instance, Alzheimer""s disease, Huntington""s disease, Parkinson""s disease, Wernicke-Korsakoff and Jakob-Creutzfeld syndromes. The action of the specific quinoxaline derivatives mentioned is attributed to the selective blocking of the NMDA and non-NMDA receptors without influencing other receptors such that the pharmaceuticals described in that document appear to be suitable only for application in glutamate-induced and glutamate-receptor-mediated neurotoxic dysfunctions, such as functional disorders of the internal ear and of the retina, and for the degenerative processes mentioned.
From Derwent Abstract, Publication No. AN 83-45789 K, the action of Caroverine and, in particular, 1-(2-dialkylaminoalkyl)-3-(p-alkoxybenzyl)-1,2-dihydroquinoxaline-2-on substances as active substances in the control of the inflow and outflow of anticancer agents can be taken, wherein the anticancer activity is developed as the anticancer agents are transferred into the cells through the cell membranes. With the usual anticancer agents, the effect will decrease in the course of time, because the cancer cells are getting resistant against the same, on the one hand, and the anticancer agents are streaming out of the cancer cells or emerge slowly from the same, on the other hand, which is impeded according to that prior art by the administration of quinoxaline derivatives, since said quinoxaline derivatives [prevent]sic the anticancer agent from flowing out of the cells, thus ensuring the retention of the high concentrations of anticancer agent within the cells.
DE-A 25 21 905 describes a medicament containing 1-diethylaminoethyl-3-(p-methoxybenzyl)-2,1,2-dihydroquinoxaline-2-on, which is said to exhibit effects on the cerebral vessels and the cerebral blood circulation.
The present invention aims at providing, in addition to the initially mentioned use of specific 1-(aminoalkyl)-3-quinoxaline-2-on derivatives, novel pharmaceutical applications and, therefore, relates to the use of 1-(aminoalkyl)-3-quinoxaline-2-on derivatives and, in particular, 1-diethylaminoethyl-3-quinoxaline-2-on derivatives of the formula 
wherein R is hydroxy, methoxy, ethoxy or hydrogen, or pharmaceutically acceptable salts thereof, for the preparation of compositions acting as antioxidants for preventing or treating diseases caused by free radicals of the oxygen cell metabolism, for stimulating the growth of nerve cells, antagonizing glutamate receptors and/or stimulating the growth of, in particular glutamatergic, nerve cells. In extensive studies on the structure of the molecules and their potential mode of action, the Applicant found that the 1-diethylaminoethyl-3-quinoxaline-2-on derivatives used according to the invention were extremely strong antioxidants and that, as a result, they exhibited, in particular, an extremely high capacity as radical interceptors, primarily vis-à-vis the hydroxyl, peroxyl and peroxynitrite radicals, which are responsible for the causation of a plurality of diseases. Their actions as antioxidants and hence as radical interceptors is attributed to the structural conditions inherent in these specific substances, which are quinoxalines with electron-rich aromatic ring systems including redoxoactive oxygen and nitrogen atoms. Due to the large number of electrons available in the molecule, it could be proved that the compounds were able to bind free radicals so as to enable the treatment, or prevent the outbreak, of diseases brought about by free radicals and, in particular, diseases brought about by free radicals of the oxygen cell metabolism, by means of the specific 1-diethylaminoethyl-3-quinoxaline-2-on derivatives used according to the invention. Moreover, it has been shown in a surprising manner that specific 1-(aminoalkyl)-3-quinoxaline-2-on derivatives and, in particular, Caroverine are capable of antagonizing metabotropic glutamate receptors. Since glutamate receptors and, in particular, metabotropic glutamate receptors have been recognized as promoters or catalysts of intracellular metabolism, Caroverine and other 1-(aminoalkyl)-3-quinoxaline-2-on derivatives are capable of antagonizing, i.e., markedly retarding, in particular, that intracellular metabolism.
Since the quinoxaline-2-on derivatives used according to the invention are known to be pharmaceutically applicable without noticeable side effects, attempts were made in the course of the studies to define and optimize the range of action of the substance as an antioxidant and radial interceptor by increasing the dose of administration. During those studies, it was surprisingly found that the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, in addition to their known activity as neuroprotective substances and on grounds of the antioxidative action discovered in the course of the studies leading to the present invention exhibit a neuroregenerative effect if administered in higher doses. This is because radicals block the intrinsic neurotrophines in a manner that, in case a radical interceptor is applied, neurotrophine activity will be reconstituted and the neuroregenerative action of the substances used according to the invention will commence. It was, therefore, feasible in the course of the studies to not only protect against further destruction damaged nerves and, in particular, nerve paths impaired or destroyed in the course of degenerative processes by neurons occurring in the central nervous system as already stated in EP-B 0 542 689, but to restore the destroyed nerve paths in a manner that, in addition to the known neuroprotective activity of such substances, also a neuroregenerative action surprisingly entered into effect, which resulted in a remarkable reduction of the signs of neurodegenerative diseases and in an improvement in the patients"" conditions.
Among the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, in particular, the hydroxy derivative 1-diethylaminoethyl-3-(p-hydroxybenzyl)-1,2-dihydroquinoxaline-2-on and the methoxy derivative 1-diethylaminoethyl-3-(p-methoxybenzyl)-1,2-dihydroquinoxyline-2-on (Caroverine) show good activities and could be administered in in vitro tests even at elevated dosages without harmful side effects on the assayed cells and in in vivo tests to test animals and patients without harmful side effects.
Due to their strong antioxidative effects, and hence their radical interceptor qualities, the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention are effective, in particular, for preventing or treating DNA alterations caused by free OH radicals and, in particular, cancer. This mode of action goes back to that one of the major biological effects of, in particular, OH radicals and ONNO radicals is the oxidation of DNA with the biological consequence of a mutation of the same and, as a result, the formation of cancer. This mode of action of, in particular, OH radicals has been investigated and demonstrated in a great number of assays. From those assays results that, due to the oncogenous effect of the OH radical on DNA, a potent OH radical interceptor, i.e., an antioxidant capable of inhibiting the oxidative effect of the OH radical on biological material is suitable as an agent for preventing and treating cancerous diseases, as suggested by the invention.
Another preferred mode of action of the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention resides in the treatment of diseases based on viral replication by free radicals of the oxygen cell metabolism and, in particular, in the inhibition of HIV replication. In studies relating to diseases based on viral replication by free radicals of the oxygen cell metabolism it was found that, upon administration of the quinoxaline derivatives used according to the invention and, in particular, Caroverine, the replication of HIV in macrophages derived from monocytes could be markedly reduced on account of the strong radical interceptor qualities of the substances used according to the invention and, in particular, Caroverine.
Due to the strong antioxidative properties of the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, their application in case of cell ageing manifestations and/or cell destructions, in particular skin ageing manifestations, caused by free radicals of the oxygen cell metabolism has proved to be particularly efficient and successful. That effect occurs both after an oxidative attack on body cells caused by chemicals and with skin cells exposed to a strong oxidizing attack due to environmental influences and, in particular, sunlight.
Allergic reactions and, in particular, type I allergies are caused, for instance, by the attack of histamine, cytokines, lipid mediators and neuromediators and currently are treated by administering antihistamines. It has now been surprisingly found that, by the exposure to histamines, cytokines, lipid mediators and neuromediators, peroxynitrite and OH radicals are released and that, by applying the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, the occurrence of secondary effects of allergies such as, e.g., inflammations and the like can be completely avoided, and also primary manifestations such as, e.g., sneezing can be stopped almost immediately upon administration of the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, because of their antioxidative properties and, in particular, radical interceptor properties.
A particularly surprising and therapeutically particularly interesting application of the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention is provided by the latter being suitable for stimulating the growth of nerve cells, in particular for restoring the functionability of, in particular glutamatergic, nerves after a cerebral stroke as well as for improving dysphagia, disturbed articulation and, in particular, speech disorders and transverse lesions of the cord with paraplegia, for treating Alzheimer""s disease, schizophrenia or amyotrophic lateral sclerosis, and for stimulating nerve growth with a cochlear implant as well as in case of functional deficits of the auditory nerve, balancing nerve, optic nerve, olfactory nerve or facial nerve.
In the course of investigations of the dosages in which the quinoxaline derivatives used according to the invention may be pharmaceutically administered to patients without serious side effects, it was surprisingly found, as already pointed out above, that the substances, in addition to their known neuroprotective action, particularly exhibit neuroregenerative actions such that the use of the compositions according to the invention in case of diseases based on the degeneration of, in particular glutamatergic, nerve cells enables the clinical picture not only to be kept stationary, as has been shown in the prior art, but, according to the invention, to be clearly improved in any event while ensuring new nerve cell growth.
It was, thus, determined, in particular in patients carrying cochlear implants for stimulating the nerves in the internal ear, that, when simultaneously administering the quinoxaline-2-on derivatives used according to the invention and, in particular Caroverine, the nerve stimulated by the implant was partially regenerated and, thereby, contacting of the implant was markedly improved, thereby clearly enhancing the audition of the thus treated patients.
It turned out to be particularly advantageous that the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives or their pharmaceutically acceptably salts, if used as antioxidants and, in particular, as radical interceptors, are applied at a daily dose ranging from 3 to 10 mg/kg and, in particular, 5 to 10 mg/kg body weight. By administering such a dose, it is feasible to markedly reduce or alleviate the symptoms of the disease without involving the occurrence of side effects due to the dosage of the medicament.
When applying the 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention, or pharmaceutically acceptable salts thereof, as neuroregenerative substances, preferably a daily dose of 3 to 20 mg/kg body weight and, in particular, 5 to 15 mg/kg body weight is employed.
At low dosages and, in particular, dosages known from the literature, of the substances and, in particular, Caroverine as neuroregenerative substance, as a calcium antagonist or even as an antioxidant, as proposed by the invention, tests and, in particular, in vitro tests have shown no neuroregenerative effect of the substance such that a high dose of the substance must be applied for obtaining the neuroregenerative effect to be reached according to the invention. In appropriate tests it was ascertained that even the high dosages proposed by the invention may be administered to patients with hardly any side effect.
The 1-(aminoalkyl)-3-quinoxaline-2-on derivatives used according to the invention may be administered in any known formulation and, in particular, orally, transdermally, topically and parenterally, intravenous administration appearing to be preferred except when used as an agent for preventing the premature ageing of skin cells.